Over the last decade cancer research has identified specific genetic lesions which induce malignant transformation and drive tumor growth. It is now recognized that mutations, deletions or alterations in the expression of normal mammalian genes involved in growth control converts these “protooncogenes” into “oncogenes”. The ras family of oncogenes consisting of H-ras, K-ras and N-ras oncogenes encode a highly conserved GTP-binding protein or Mr=21,000 (p21).
Oncogenes frequently encode components of signal transduction pathways which lead to stimulation of cell growth and mitogenesis. Oncogene expression in cultured cells leads to cellullar transformation, characterized by the ability of cells to grow in soft agar and the growth of cells as dense foci lacking the contact inhibition exhibited by non-transformed cells. Mutation and/or overexpression of certain oncogenes is frequently associated with human cancer. In order to acquire transforming potential the precursor of the ras oncoprotein must undergo farnesylation of the cysteine residue located in a carboxyl-terminal tetrapeptide. Inhibitors of the enzyme that catalyzes this modification, farnesyl protein tranferase, have therefore been suggested as anticancer agents for tumors in which ras contributes to transformation. Mutated oncogenic forms of ras are frequently found in many human cancers, most notably in more than 50% of colon and pancreatic carcinomas (Kohl et al., Science, vol. 260, 1384 to 1837, 1993).
The protein products of the ras ocogenes have been the focus of oncology drug discovery efforts because of some unique features of the cellular metabolism of these proteins. To function in signal transduction and cell transformation, ras must attach to the plasma membrane to promote interactions with membrane localization also SH2/SH3 domain adaptor proteins Grb2 and SOS. Ras membrane localization also functions in the activation of downstream effectors such as Raf protein kinase. Newly synthesized Ras proteins must pe posttranslationally modified in mammalian cells by farnesylation followed by the proteolytiac cleavage of the three terminal amino acids and carboxy-O-methylation to produce the hydrophobicity or recognition sites which allow proper membrane localization. The initial and rate-limiting post-translational modification of Ras involves the covalent attachment of farnesol via a thioether linkage to a single cysteine residue positioned four amino acids from the carboxy terminus of the protein. This reaction is catalyzed by farnesyl protein transferase (FPT). The enzyme requires only the four C-terminal amino acids or CAAX motif for specific binding and catalysis of protein substrates.
Farnesyl protein transferase inhibitors have been described as being useful in the treatment of mammalian cancers and in particular in the treatment of colon and pancreatic cancers.
WO-97/21701, and it's United States counterpart, U.S. Pat. No. 6,037,350, describe the preparation, formulation and pharmaceutical properties of farnesyl protein transferase inhibiting (imidazoly-5-yl)methyl-2-quinolinone derivatives of formulas (I), (II) and (III), as well as intermediates of formula (II) and (III) that are metablolized in vivo to the compounds of formula (I). The compounds of formulas (I), (II) and (III) are represented by the pharmaceutically acceptable acid or base addition salts and the stereochemically isomeric forms thereof, wherein                the dotted line represents an optional bond;        X is oxygen or sulfur;        R1 is hydrogen, C1-12alkyl, Ar1, Ar2C1-6alkyl, quinolinylC1-6alkyl, pyridylC1-6alkyl, hydroxyC1-6alkyl, C1-6alkyloxyC1-6alkyl, mono- or di(C1-6alkyl)aminoC1-6alkyl, aminoC1-6alkyl,                    or a radical of formula —Alk1—C(═O)—R9, —Alk1—S(O)-R9 or —Alk1—S(O)2—R9, wherein Alk1 is C1-6alkanediyl,                            R9 is hydroxy, C1-6alkyl, C1-6alkyloxy, amino, C1-8alkylamino or C1-8alkylamino substituted with C1-6alkyloxycarbonyl;                                                R2, R3 and R16 each independently are hydrogen, hydroxy, halo, cyano, C1-6alkyl, C1-6alkyloxy, hydroxyC1-6alkyloxy, C1-6alkyloxyC1-6alkyloxy, aminoC1-6alkyl-oxy, mono- or di(C1-6alkyl)aminoC1-6alkyloxy, Ar1, Ar2C1-6alkyl, Ar2oxy, Ar2C1-6alkyloxy, hydroxycarbonyl, C1-6alkyloxycarbonyl, trihalomethyl, trihalomethoxy, C2-6alkenyl, 4,4-dimethyloxazolyl; or                    when on adjacent positions R2 and R3 taken together may form a bivalent radical of formula—O—CH2—O—  (a-1) —O—CH2—CH2—O—  (a-2) —O—CH═CH—  (a-3) —O—CH2—CH2—  (a-4) —O—CH2—CH2—CH2—  (a-5) or —CH═CH—CH═CH—  (a-6)                         R4 and R5 each independently are hydrogen, halo, Ar1, C1-6alkyl, hydroxyC1-6alkyl, C1-6alkyloxyC1-6alkyl, C1-6alkyloxy, C1-6alkylthio, amino, hydroxycarbonyl, C1-6alkyloxycarbonyl, C1-6alkylS(O)C1-6alkyl or C1-6alkylS(O)2C1-6alkyl;        R6 and R7 each independently are hydrogen, halo, cyano, C1-6alkyl, C 1-6alkyloxy, Ar2oxy, trihalomethyl, C1-6alkylthio, di(C1-6alkyl)amino, or                    when on adjacent positions R6 and R7 taken together may form a bivalent radical of formula—O—CH2—O—  (c-1) or —CH═CH—CH═CH—  (c-2)                         R8 is hydrogen, C1-6alkyl, cyano, hydroxycarbonyl, C1-6alkyloxycarbonyl, C1-6alkylcarbonylC1-6alkyl, cyanoC1-6alkyl, C1-6alkyloxycarbonylC1-6alkyl, carboxyC1-6alkyl, hydroxyC1-6alkyl, aminoC1-6alkyl, mono- or di(C1-6alkyl)-aminoC1-6alkyl, imidazolyl, haloC1-6alkyl, C1-6alkyloxyC1-6alkyl, aminocarbonylC1-6alkyl, or a radical of formula—O—R10  (b-1) —S—R10  (b-2) —N—R11R12  (b-3)         wherein R10 is hydrogen, C1-6alkyl, C1-6alkylcarbonyl, Ar1, Ar2C1-6alkyl, C1-6alkyloxycarbonyl-C1-6alkyl, or a radical or formula —Alk2—OR13 or —Alk2—NR14R15;        R11 is hydrogen, C1-12alkyl, Ar1 or Ar2C1-6alkyl;        R12 is hydrogen, C1-6alkyl, C1-6alkylcarbonyl, C1-6alkyloxycarbonyl, C1-6alkylaminocarbonyl, Ar1, Ar2C1-6alkyl, C1-6alkylcarbonyl-C1-6alkyl, a natural amino acid, Ar1carbonyl, Ar2C1-6alkylcarbonyl, aminocarbonylcarbonyl, C1-6alkyloxyC1-6alkylcarbonyl, hydroxy, C1-6alkyloxy, aminocarbonyl, di(C1-6alkyl)aminoC1-6alkylcarbonyl, amino, C1-6alkylamino, C1-6alkylcarbonylamino, or a radical or formula —Alk2—OR13 or —Alk2—NR14R15;        wherein Alk2 is C1-6alkanediyl;                    R13 is hydrogen, C1-6alkyl, C1-6alkylcarbonyl, hydroxy-C1-6alkyl, Ar1 or Ar2C1-6alkyl;            R14 is hydrogen, C1-6alkyl, Ar1 or Ar2C1-6alkyl;            R15 is hydrogen, C1-6alkyl, C1-6alkylcarbonyl, Ar1 or Ar2C1-6alkyl;                        R17 is hydrogen, halo, cyano, C1-6alkyl, C1-6alkyloxycarbonyl, Ar1;        R18 is hydrogen, C1-6alkyl, C1-6alkyloxy or halo;        R19 is hydrogen or C1-6alkyl;        Ar1 is phenyl or phenyl substituted with C1-6alkyl, hydroxy, amino, C1-6alkyloxy or halo; and        Ar2 is phenyl or phenyl substituted with C1-6alkyl, hydroxy, amino, C1-6alkyloxy or halo.        
WO-97/16443, and it's United States counterpart, U.S. Pat. No. 5,968,952, concern the preparation, formulation and pharmaceutical properties of farnesyl protein transferase inhibiting compounds of formula (IV), as well as intermediates of formula (V) and (VI) that are metabolized in vivo to the compounds of formula (IV). The compounds of formulas (IV), (V) and (VI) are represented by the pharmaceutically acceptable acid or base addition salts and the stereochemically isomeric forms thereof, wherein                the dotted line represents an optional bond;        X is oxygen or sulfur;        R1 is hydrogen, C1-12alkyl, Ar1, Ar2C1-6alkyl, quinolinylC1-6alkyl, pyridyl-C1-6alkyl, hydroxyC1-6alkyl, C1-6alkyloxyC1-6alkyl, mono- or di(C1-6alkyl)-aminoC1-6alkyl, aminoC1-6alkyl,                    or a radical of formula -—Alk1—C(═O)—R9, —Alk1—S(O)—R9 or —Alk1—S(O)2—R9,            wherein Alk1 is C1-6alkanediyl,                            R9 is hydroxy, C1-6alkyl, C1-6alkyloxy, amino, C1-8alkylamino or C1-8alkylamino substituted with C1-6alkyloxycarbonyl;                                                R2 and R3 each independently are hydrogen, hydroxy, halo, cyano, C1-6alkyl, C1-6alkyloxy, hydroxyC1-6alkyloxy, C1-6alkyloxyC1-6alkyloxy, amino-C1-6alkyloxy, mono- or di(C1-6alkyl)aminoC1-6alkyloxy, Ar1, Ar2C1-6alkyl, Ar2oxy, Ar2C1-6alkyloxy, hydroxycarbonyl, C1-6alkyloxycarbonyl, trihalomethyl, trihalomethoxy, C2-6alkenyl; or                    when on adjacent positions R2 and R3 taken together may form a bivalent radical of formula—O—CH2—O—  (a-1) —O—CH2—CH2—O—  (a-2) —O—CH═CH—  (a-3)  —O—CH2—CH2—  (a-4)—O—CH2—CH2—CH2—  (a-5) or—CH═CH—CH═CH—  (a-6)                         R4 and R5 each independently are hydrogen, Art, C1-6alkyl, C1-6alkyloxyC1-6alkyl, C1-6alkyloxy, C1-6alkylthio, amino, hydroxycarbonyl, C1-6alkyloxycarbonyl, C1-6alkylS(O)C1-6alkyl or C1-6alkylS(O)2C1-6alkyl;        R6 and R7 each independently are hydrogen, halo, cyano, C1-6alkyl, C1-6alkyloxy or Ar2oxy;        R8 is hydrogen, C1-6alkyl, cyano, hydroxycarbonyl, C1-6alkyloxycarbonyl, C1-6alkyl-carbonylC1-6alkyl, cyanoC1-6alkyl, C1-6alkyloxycarbonylC1-6alkyl, hydroxy-carbonylC1-6alkyl, hydroxyC1-6alkyl, aminoC1-6alkyl, mono- or di(C1-6alkyl)-aminoC1-6alkyl, haloC1-6alkyl, C1-6alkyloxyC1-6alkyl, aminocarbonylC1-6alkyl, Ar1, Ar2C1-6alkyloxyC1-6alkyl, C1-6alkylthioC1-6alkyl;        R10 is hydrogen, C1-6alkyl, C1-6alkyloxy or halo;        R11 is hydrogen or C1-6alkyl;        Ar1 is phenyl or phenyl substituted with C1-6alkyl, hydroxy, amino, C1-6alkyloxy or halo;        Ar2 is phenyl or phenyl substituted with C1-6alkyl, hydroxy, amino, C1-6alkyloxy or halo.        
WO-98/40383, and it's United States counterpart, U.S. Pat. No. 6,187,786, concern the preparation, formulation and pharmaceutical properties of farnesyl protein transferase inhibiting compounds of formula (VII) the pharmaceutically acceptable acid addition salts and the stereochemically isomeric forms thereof, wherein                the dotted line represents an optional bond;        X is oxygen or sulfur;        —A— is a bivalent radical of formula        
—CH═CH—(a-1),—CH2—S—(a-6),—CH2—CH2—(a-2),—CH2—CH2—S—(a-7),—CH2—CH2—CH2—(a-3),—CH═N—(a-8),—CH2—O—(a-4),—N═N—(a-9), or—CH2—CH2—O—(a-5),—CO—NH—(a-10);                wherein optionally one hydrogen atom may be replaced by C1-4alkyl or Ar1;        
R1 and R2 each independently are hydrogen, hydroxy, halo, cyano, C1-6alkyl, trihalomethyl, trihalomethoxy, C2-6alkenyl, C1-6alkyloxy, hydroxyC1-6alkyloxy, C1-6alkyloxyC1-6alkyloxy, C1-6alkyloxycarbonyl, aminoC1-6alkyloxy, mono- or di(C1-6alkyl)aminoC1-6alkyloxy, Ar2, Ar2-C1-6alkyl, Ar2-oxy, Ar2—C1-6alkyloxy; or when on adjacent positions R1 and R2 taken together may form a bivalent radical of formula—O—CH2—O—  (b-1) —O—CH2—CH2—O—  (b-2) —O—CH═CH—  (b-3) —O—CH2—CH2—  (b-4) —O—CH2—CH2—CH2—  (b-5) or—CH═CH—CH═CH—  (b-6) 
R3 and R4 each independently are hydrogen, halo, cyano, C1-6alkyl, C1-6alkyloxy, Ar3-oxy, C-6alkylthio, di(C1-6alkyl) amino, trihalomethyl, trihalomethoxy, or when on adjacent positions R3 and R4 taken together may form a bivalent radical of formula—O—CH2—O—  (c-1) —O—CH2—CH2—O—  (c-2) or—CH═CH—CH═CH—  (c-3) 
R5 is a radical of formula                 wherein R13 is hydrogen, halo, Ar4, C1-6alkyl, hydroxyC1-6alkyl, C1-6alkyloxy-C1-6alkyl, C1-6alkyloxy, C1-6alkylthio, amino, C1-6alkyloxy-carbonyl, C1-6alkylS(O)C1-6alkyl or C1-6alkylS(O)2C1-6alkyl;        R14is hydrogen, C1-6alkyl or di(C1-4alkyl)aminosulfonyl;        
R6 is hydrogen, hydroxy, halo, C1-6alkyl, cyano, haloC1-6alkyl, hydroxyC1-6alkyl, cyanoC1-6alkyl, aminoC1-6alkyl, C1-6alkyloxyC1-6alkyl, C1-6alkylthioC1-6alkyl, aminocarbonylC1-6alkyl, C1-6alkyloxycarbonylC1-6alkyl, C1-6alkylcarbonyl-C1-6alkyl, C1-6alkyloxycarbonyl, mono- or di(C1-6alkyl)aminoC1-6alkyl, Ar5, Ar5—C1-6alkyloxyC1-6alkyl; or a radical of formula—O—R7  (e-1) —S—R7  (e-2) —N—R8R9  (e-3)                 wherein R7 is hydrogen, C1-6alkyl, C1-6alkylcarbonyl, Ar6, Ar6—C1-6alkyl, C1-6alkyloxycarbonylC1-6alkyl, or a radical of formula —Alk—OR10 or —Alk—NR11R12;                    R8 is hydrogen, C1-6alkyl, Ar7 or Ar7—C1-6alkyl;            R9 is hydrogen, C1-6alkyl, C1-6alkylcarbonyl, C1-6alkyloxycarbonyl, C1-6alkylaminocarbonyl, Ar8, Ar8—C1-6alkyl, C1-6alkylcarbonyl-C1-6alkyl, Ar8-carbonyl, Ar8-C1-6alkylcarbonyl, aminocarbonylcarbonyl, C1-6alkyloxyC1-6alkylcarbonyl, hydroxy, C1-6alkyloxy, aminocarbonyl, di(C1-6alkyl)aminoC1-6alkylcarbonyl, amino, C1-6alkylamino, C1-6alkylcarbonylamino,                            or a radical or formula —Alk—OR10 or —Alk—NR11R12;                                                wherein Alk is C1-6alkanediyl;                    R10 is hydrogen, C1-6alkyl, C1-6alkylcarbonyl, hydroxy-C1-6alkyl, Ar9 or Ar9—C1-6alkyl;            R11 is hydrogen, C1-6alkyl, C1-6alkylcarbonyl, Ar10 or Ar10—C1-6alkyl;            R 12 is hydrogen, C1-6alkyl, Ar11 or Ar11—C1-6alkyl; and                        Ar1 to Ar11 are each independently selected from phenyl; or phenyl substituted with halo, C1-6alkyl, C1-6alkyloxy or trifluoromethyl.        
WO-98/49157 and it's United States counterpart, U.S. Pat. No. 6,177,432, concern the preparation, formulation and pharmaceutical properties of farnesyl protein transferase inhibiting compounds of formula (VIII). the pharmaceutically acceptable acid addition salts and the stereochemically isomeric forms thereof, wherein                the dotted line represents an optional bond;        
X is oxygen or sulfur;
R1 and R2 each independently are hydrogen, hydroxy, halo, cyano, C1-6alkyl, trihalomethyl, trihalomethoxy, C2-6alkenyl, C1-6alkyloxy, hydroxyC1-6alkyloxy, C1-6alkyloxyC1-6alkyloxy, C1-6alkyloxycarbonyl, aminoC1-6alkyloxy, mono- or di(C1-6alkyl)aminoC1-6alkyloxy, Ar1, Ar1C1-6alkyl, Ar1oxy or Ar1C1-6alkyloxy;
R3 and R4 each independently are hydrogen, halo, cyano, C1-6alkyl, C1-6alkyloxy, Ar1oxy, C1-6alkylthio, di(C1-6alkyl)amino, trihalomethyl or trihalomethoxy;
R5 is hydrogen, halo, C1-6alkyl, cyano, haloC1-6alkyl, hydroxyC1-6alkyl, cyanoC1-6alkyl, aminoC1-6alkyl, C1-6alkyloxyC1-6alkyl, C1-6alkylthioC1-6alkyl, aminocarbonylC1-6alkyl, C1-6alkyloxycarbonylC1-6alkyl, C1-6alkylcarbonyl-C1-6alkyl, C1-6alkyloxycarbonyl, mono- or di(C1-6alkyl)aminoC1-6alkyl, Ar1, Ar1C1-6alkyloxyC1-6alkyl; or a radical of formula—O—R10  (a-1) —S—R10  (a-2) —N—R11R12  (a-3)                 wherein R10 is hydrogen, C1-6alkyl, C1-6alkylcarbonyl, Ar1, Ar1C1-6alkyl, C1-6alkyloxycarbonylC1-6alkyl, or a radical of formula —Alk—OR13 or —Alk—NR14R15;                    R11 is hydrogen, C1-6alkyl, Ar1 or Ar1C1-6alkyl;            R12 is hydrogen, C1-6alkyl, C1-6alkylcarbonyl, C1-6alkyloxycarbonyl, C1-6alkylaminocarbonyl, Ar1, Ar1C1-6alkyl, C1-6alkylcarbonyl-C1-6alkyl, Ar1carbonyl, Ar1C1-6alkylcarbonyl, aminocarbonylcarbonyl, C1-6alkyloxyC1-6alkylcarbonyl, hydroxy, C1-6alkyloxy, aminocarbonyl, di(C1-6alkyl)aminoC1-6alkylcarbonyl, amino, C1-6alkylamino, C1-6alkylcarbonylamino,            or a radical or formula —Alk—OR13 or —Alk—NR14R15;            wherein Alk is C1-6alkanediyl;                            R13 is hydrogen, C1-6alkyl, C1-6alkylcarbonyl, hydroxy-C1-6alkyl, Ar1 or Ar1C1-6alkyl;                R14 is hydrogen, C1-6alkyl, Ar1 or Ar1C1-6alkyl;                R15 is hydrogen, C1-6alkyl, C1-6alkylcarbonyl, Ar1 or Ar1C1-6alkyl;                                                
R6 is a radical of formula                 wherein R16is hydrogen, halo, Ar1, C1-6alkyl, hydroxyC1-6alkyl, C1-6alkyloxy-C1-6alkyl, C1-6alkyloxy, C1-6alkylthio, amino, C1-6alkyloxycarbonyl, C1-6alkylthioC1-6alkyl, C1-6alkylS(O)C1-6alkyl or C1-6alkylS(O)2C1-6alkyl;                    R17is hydrogen, C1-6alkyl or di(C1-4alkyl)aminosulfonyl;                        
R7 is hydrogen or C1-6alkyl provided that the dotted line does not represent a bond;
R8 is hydrogen, C1-6alkyl or Ar2CH2 or Het1CH2;
R9 is hydrogen, C1-6alkyl , C1-6alkyloxy or halo; or
R8 and R9 taken together to form a bivalent radical of formula—CH═CH—  (c-1) —CH2—CH2—  (c-2) —CH2—CH2—CH2—  (c-3) —CH2—O—  (c-4) or—CH2—CH2—O—  (c-5) 
Ar1 is phenyl; or phenyl substituted with 1 or 2 substituents each independently selected from halo, C1-6alkyl, C1-6alkyloxy or trifluoromethyl;
Ar2 is phenyl; or phenyl substituted with 1 or 2 substituents each independently selected from halo, C1-6alkyl, C1-6alkyloxy or trifluoromethyl; and
Het1 is pyridinyl; pyridinyl substituted with 1 or 2 substituents each independently selected from halo, C1-6alkyl, C1-6alkyloxy or trifluoromethyl.
WO-00/39082, and it's United States counterpart, U.S. patent application Ser. No. 09/868,992, flied Aug. 29, 2001, concern the preparation, formulation and pharmaceutical properties of farnesyl protein transferase inhibiting compounds of formula (IX) or the pharmaceutically acceptable acid addition salts and the stereochemically isomeric forms thereof, wherein                ═X1—X2—X3— is a trivalent radical of formula        
═N—CR6═CR7—(x-1),═CR6—CR7═CR8—(x-6),═N—N═CR6—(x-2),═CR6—N═CR7—(x-7),═N—NH—C(═O)—(x-3),═CR6—NH—C(═O)—(x-8), or═N—N═N—(x-4),═CR6—N═N—(x-9);═N—CR6═N—(x-5),                wherein each R6, R7 and R8 are independently hydrogen, C1-4alkyl, hydroxy, C1-4alkyloxy, aryloxy, C1-4alkyloxycarbonyl, hydroxyC1-4alkyl, C1-4alkyloxyC1-4alkyl, mono- or di(C1-4alkyl)aminoC1-4alkyl, cyano, amino, thio, C1-4alkylthio, arylthio or aryl;        
>Y1-Y2 is a trivalent radical of formula>CH—CHR9—  (y-1) >C═N—  (y-2) >CH—NR9—  (y-3) or>C═CR9—  (y-4)                 wherein each R9 independently is hydrogen, halo, halocarbonyl, aminocarbonyl, hydroxyC1-4alkyl, cyano, carboxyl, C1-4alkyl, C1-4alkyloxy, C1-4alkyloxyC1-4alkyl, C1-4alkyloxycarbonyl, mono- or di(C1-4alkyl)amino, mono- or di(C1-4alkyl)aminoC1-4alkyl, aryl;        r and s are each independently 0, 1, 2, 3, 4 or 5;        t is 0, 1, 2 or 3;        each R1 and R2 are independently hydroxy, halo, cyano, C1-6alkyl, trihalomethyl, trihalomethoxy, C2-6alkenyl, C1-6alkyloxy, hydroxyC1-6alkyloxy, C1-6alkylthio, C1-6alkyloxyC1-6alkyloxy, C1-6alkyloxycarbonyl, aminoC1-6alkyloxy, mono- or di(C1-6alkyl)amino, mono- or di(C1-6alkyl)aminoC1-6alkyloxy, aryl, arylC1-6alkyl, aryloxy or arylC1-6alkyloxy, hydroxycarbonyl, C1-6alkyloxycarbonyl, aminocarbonyl, aminoC1-6alkyl, mono- or di(C1-6alkyl)aminocarbonyl, mono- or di(C1-6alkyl)aminoC1-6alkyl; or        two R1 or R2 substituents adjacent to one another on the phenyl ring may independently form together a bivalent radical of formula—O—CH2—O—  (a-1) —O—CH2—CH2—O—  (a-2) —O═CH═CH—  (a-3) —O—CH2—CH2—  (a-4) —O—CH2—CH2—CH2—  (a-5) or—CH═CH—CH═CH—  (a-6)         
R3 is hydrogen, halo, C1-6alkyl, cyano, haloC1-6alkyl, hydroxyC1-6alkyl, cyanoC1-6alkyl, aminoC1-6alkyl, C1-6alkyloxyC1-6alkyl, C1-6alkylthioC1-6alkyl, aminocarbonylC1-6alkyl, hydroxycarbonyl, hydroxycarbonylC1-6alkyl, C1-6alkyloxycarbonylC1-6alkyl, C1-6alkylcarbonylC1-6alkyl, C 1-6alkyloxycarbonyl, aryl, arylC1-6alkyloxyC1-6alkyl, mono- or di(C1-6alkyl)aminoC1-6alkyl;                or a radical of formula—O—R10  (b-1) —S—R10  (b-2) —NR11R12  (b-3)         wherein R10 is hydrogen, C1-6alkyl, C1-6alkylcarbonyl, aryl, arylC1-6alkyl, C1-6alkyloxycarbonylC1-6alkyl, or a radical of formula —Alk—OR13 or —Alk—NR14R15;                    R11 is hydrogen, C1-6alkyl, aryl or arylC1-6alkyl;            R12 is hydrogen, C1-6alkyl, aryl, hydroxy, amino, C1-6alkyloxy, C1-6alkylcarbonylC1-6alkyl, arylC1-6alkyl, C1-6alkylcarbonylamino, mono- or di(C1-6alkyl)amino, C1-6alkylcarbonyl, aminocarbonyl, arylcarbonyl, haloC1-6alkylcarbonyl, arylC1-6alkylcarbonyl,            C1-6alkyloxycarbonyl, C1-6alkyloxyC1-6alkylcarbonyl, mono- or di(C1-6alkyl)aminocarbonyl wherein the alkyl moiety may optionally be substituted by one or more substituents independently selected from aryl or C1-3alkyloxycarbonyl, aminocarbonylcarbonyl, mono- or di(C1-6alkyl)aminoC1-6alkylcarbonyl, or a radical or formula —Alk—OR13 or —Alk—NR14R15;                        wherein Alk is C1-6alkanediyl;                    R13 is hydrogen, C1-6alkyl, C1-6alkylcarbonyl, hydroxyC1-6alkyl, aryl or arylC1-6alkyl;            R14 is hydrogen, C1-6alkyl, aryl or arylC1-6alkyl;            R15 is hydrogen, C1-6alkyl, C1-6alkylcarbonyl, aryl or arylC1-6alkyl;                        R4 is a radical of formula         wherein R16 is hydrogen, halo, aryl, C1-6alkyl, hydroxyC1-6alkyl, C1-6aikyloxyC1-6alkyl, C1-6alkyloxy, C1-6alkylthio, amino, mono- or di(C1-4alkyl)amino, hydroxycarbonyl, C1-6alkyloxycarbonyl, C1-6alkylthioC1-6alkyl, C1-6alkylS(O)C1-6alkyl or C1-6alkylS(O)2C1-6alkyl;                    R16 may also be bound to one of the nitrogen atoms in the imidazole ring of formula (c-1) or (c-2), in which case the meaning of R16 when bound to the nitrogen is limited to hydrogen, aryl, C1-6alkyl, hydroxyC1-6alkyl, C1-6alkyloxyC1-6alkyl, C1-6alkyloxycarbonyl, C1-6alkylS(O)C1-6alkyl or C1-6alkylS(O)2C1-6alkyl;            R17 is hydrogen, C1-6alkyl, C1-6alkyloxyC1-6alkyl, arylC1-6alkyl, trifluoromethyl or di(C1-4alkyl)aminosulfonyl;                        
R5 is C1-6alkyl , C1-6alkyloxy or halo;                aryl is phenyl, naphthalenyl or phenyl substituted with 1 or more substituents each independently selected from halo, C1-6alkyl, C1-6alkyloxy or trifluoromethyl.        
Other useful farnesyl protein transferase inhibitors include Arglabin (i.e.1(R)-10-epoxy-5(S),7(S)-guaia-3(4),11(13)-dien-6,12-olide descibed in WO-98/28303 (NuOncology Labs); perrilyl alcohol described in WO-99/45912 (Wisconsin Genetics); SCH-66336, i.e. (+)-(R)-4-[2-[4-(3,10-dibromo-8-chloro-5,6-dihydro-11H-benzo[5,6]cyclohepta[1,2-b]pyridin-11-yl)piperidin-1-yl]-2-oxoethyl]piperidine-1-carboxamide, described in U.S. Pat. No. 5874442 (Schering); L778123, i.e. 1-(3-chlorophenyl)-4-[1-(4-cyanobenzyl)-5-imidazolylmethyl]-2-piperazinone, described in WO-00/01691 (Merck); compound 2(S)-[2(S)-[2(R)-amino-3-mercapto]propylamino-3(S)-methyl]-pentyloxy-3-phenylpropionyl-methionine sulfone described in WO-94/10138 (Merck); and BMS 214662, i.e. (R)-2,3,4,5-tetrahydro-1-(1H-imidazol-4-ylmethyl)-3-(phenylmethyl)-4-(2-thienylsulphonyl)-1H-1,4-benzodiazapine-7-carbonitrile, described in WO 97/30992 (Bristol Myers Squibb) and Pfizer compounds (A) and (B) described in WO-00/12498 and WO-00/12499: 
The compounds are generally described as being inhibitors of farnesyl protein transferase useful in the treatment of mammalian tumors. Generally in the treatment of cancerous tumors about 0.01 mg/kg to 100 mg/kg body weight of a farnesyl protein transferase inhibitor is administered at doses of about two, three, four or more sub doses at appropriate intervals throughout the day. This dosing schedule is predicated on the hypothesis that continuous exposure to the active compound and resultant inhibition of FPT were required in order to maintain antitumor effects.
Unexpectedly, it has been found that an interrupted dosing regimen of about five days containing a farnesyl protein transferase inhibitor as the active ingredient followed by about two weeks without treatment results in suppression of mammalian tumor growth.
It is an object of the present invention to provide a method of treatment and a dosing regimen comprising a discontinuous dosing schedule in which a farnesyl protein transferase inhibitor is administered to suppress mammalian tumor growth. The regimen comprises the administration of a single dose of a farnesyl protein transferase inhibitor over a one to five day period followed by at least two weeks without treatment.